Basic Biology of Brain Metastasis

Brain metastases (BMs) occur through a coordinated process whereby cancer cells detach from a primary cancer site and hematogenously spread to, colonize, and grow in the central nervous system (CNS). As systemic therapies improve, the clinical importance of CNS metastases for overall survival and quality of life of cancer patients becomes increasingly important. In this chapter, we review basic biological concepts associated with CNS metastases with an emphasis on brain metastases (BMs). Although many significant advances have been achieved, our understanding of the basic biology of CNS metastases is still incomplete and evolving. The effective clinical management of CNS metastases relies heavily on leveraging current and future understanding of basic mechanisms driving CNS metastases to achieve better control and quality of life. Here we review foundational concepts of “seed and soil” hypothesis and EMT/MET (epithelial-mesenchymal transition/mesenchymal-epithelial transition), which provide conceptual frameworks for understanding the clinical profile of CNS metastases and underlying cellular-molecular mechanisms regulating brain and CNS metastases, respectively. In addition, we will address the importance of cancer stem cells (CSCs), molecular heterogeneity, the immune and tumor microenvironment (metastatic niche), and the use of liquid biopsies to detect circulating tumor cells (CTCs), exosomes, and cell-free DNA (cfDNA). Deciphering how complex sequential mechanisms and the architecture of brain microenvironment drive the metastatic cascade and promote tumor survival, growth, and treatment resistance is critical to the development of more effective targeted therapies.